Electrospun Gelatin Meshes with Multifactor Release to Promote Bone Regeneration and Prevent Infection Bone grafts account for over 500,000 surgeries each year in the United States with the number of surgeries expected to rise due to an aging population. Although small defects may be repaired using autografts, large defects require treatment with allografts or synthetic grafts, which have a ten-year failure rate as high as 60%. Poor outcomes arise from non-unions due to inadequate vascularization, lack of osteoinduction, and post-operative infection. Although research has made significant improvements in understanding graft failure and overcoming single failure modalities, there is still a need to develop advanced treatments that address multiple obstacles simultaneously. The central hypothesis for this proposal is that clinical outcomes of bone grafting procedures can be improved with the addition of a mesh that both prevents infection and enhances bone healing through endogenous cell recruitment and vascularization. This multifactorial approach requires a single material capable of targeting multiple therapeutic pathways, each with optimal release profiles. To this end, we have developed a co-spinning process with in situ crosslinking of gelatin fibers using two synthetic modalities to generate electrospun meshes with multiple fiber populations, each with independent crosslinking. The mechanisms release embedded or tethered molecules at rates dependent on the crosslink density. The material allows for a range of fast (hours) to slow release (weeks) leading to a multitude of applications as a thin outer layer with temporal drug delivery of several factors. The investigative team has the necessary expertise in bone tissue engineering, electrospinning (Cosgriff-Hernandez), and anti-microbial studies (Cohen). Upon completion, the multifunctional meshes will have passed the initial in vitro screening to permit assessment of allograft revitalization in rodent and large animal models (future R01). Although initially focused on improving bone regeneration, there is broad potential applications in regenerative medicine where multifactor release with independent control of release kinetics of growth factors, anti-inflammatories, or enzymes.